Nitric oxide (NO), has been shown to have profound effects on the function of leukocytes and in the overall host immune response to infection, sepsis and septic shock. NO is synthesized by three different isoforms of NO synthase (NOS), two are constitutively expressed (NOS1 and NOS3) and another (NOS2) that is inducible with specific stimulus. Although most studies of the role of NOS and NO in sepsis have focused on the inducible isoform, less is known about the role of NOS1 in sepsis. There is some evidence to suggest that NOS1 might have a very important role in the host response to infection. The enzyme is constitutively expressed not only in neuronal cells in the brain and spinal cord, but also in the microvasculature and epithelium of the gastrointestinal tract and kidney, bronchial epithelium, myocytes of skeletal muscle, mast cells in skin, and neutrophils. Under baseline conditions and during sterile peritonitis, mice congenitally lacking NOS1 (NOS1-deficient) have increased leukocyte rolling and adhesion to the endothelium of postcapillary venules and increased leukocyte migration into the peritoneal cavity. We are investigating the effects of NOS1 on extravascular neutrophil recruitment, bacterial clearance, and inflammatory tissue injury during polymicrobial peritonitis, sepsis, and septic shock. At baseline, NOS1-deficient animals have higher neutrophil and lower platelet counts compared with wild type animals. We found that, although NOS1-deficient animals have reported increased migration of neutrophils into the peritoneum, in the setting of live bacterial peritonitis and sepsis, genetic deficiency of NOS1 is detrimental and increased mortality. Such detrimental effect in survival was also seen in a model of lipopolysaccharide (LPS) challenge. The mechanisms of this increased mortality in NOS1-deficient animals are yet unknown but it appears that NOS1-deficient have higher systemic bacterial counts in blood compared to wild type animals suggesting that animals deficient in NOS1 may have decreased bacterial clearance. We are now studying the mechanism whereby NOS1 impacts on survival and bacterial clearance during sepsis and septic shock. Studies to further elucidate the role of NOS1 in sepsis include examining the how the lack of NOS1 impacts on neutrophil activation and function. In addition we are evaluating the effects of NOS1 on lymphocyte function.